Organic arsenic compounds



Patented Oct. 12, 1943 ORGANIC ARSENIC COMPOUNDS Cliff 8. Hamilton, Lincoln, Nehru, assignor. to

Parke, Davis & Company, Detroit, Mich.,a corporation of Michigan No Drawing. Application. May 21, 1946, Serial No. 336,440

Claims.

This invention isconcerned. with the formation, of new organic arsenic compounds. More specifically, it relates to arsine oxides and other trivalent arsenic forms in which the arsenic is attached to the benzene ring.

Many aromatic arsine oxides have been prepared with various substituents in, the benzene ring, including several of the theoretically possible isomers containing the hydroxyl and amino.

AsZ

NHY

where X represent one of hydrogen, methyl or hydroxy alkyl; Y stands for hydrogen, or carboalkoxy, carboaralkoxy or the corresponding soluble amine salt group, Y'HA, where A is an anion of an acid, HA. In the above formula, AsZ represents a member of the class As=O, AsCl2,

.AS(SCH2COOM) 2 and -TAS (SCH2 COrNHz) 2,

M being a, soluble salt forming, group such as alkali metal or ammonium or substituted ammonium radicals.

The production of arsine oxides has generally been achieved by certain well known procedures for reducing the parent arsonic acids. However, previous workers have found that the usual reducing agents cause 2-hydroXy-4-amin0phenyl arsonic acid to dearsonate (split off arsenic from the organic molecule) or form polyarsenos (complex higher molecular weight reduction products) Some cases of dearsonation ofthis arsonic acid have been reported by Beguin &, Hamilton, J. A. C. S. 61, 355 (1939).

In preparing these oxides and oxide derivatives, therefore, reaction conditions had to be sought that would not cause dearsonation to, occur. 7

I have found that in preparing someof the, compounds of this invention it is necessary toavoid the use of hydrochloric and'hydrobromic acids to prevent dearsonation or formation of complex compounds of uncertain structure and composition. I I

I have also found that certain of the. com; pounds of the invention may be prepared in the, presence of hydrochloric or hydrobromic acid without causing dearsonation or like undesirable reaction.

The compounds of the invention are valuable for chemotherapeutic purposes-and also as intermediates for the preparation of compounds in tended for such purposes, The invention also includes new compounds which were previously unknown.

The invention is illustrated by the following examples.

Five grams of 2-hydroxy-4-aminophenylarsonic acid are dissolved in mhof 2N sulfuric acid bywarmin rdl g. of potassium iodide added and, the solution saturated with sulfur dioxidefor.

six hours.) After standing overnight the solution.

is v boiled under reduced pressure to'remove the, excess sulfur dioxide, keeping the temperature, under 40 C. The solution is then made alkaline, with ammonia water and taken'to dryness on; a steam bath under reduced pressure. The solid material is triturated with water and the. sus,-. pended oxide filtered from the solution oi ino r.-. ganic salts. The oxide obtained in this Way is; nearly pure. The oxide may be purified further by solution in an appropriate alkaline media such as sodium carbonate or sodium hydroxide, charcoaling, filtering and re-isolating by neutralizing with sulfuric acid, making slightly alkaline with. ammonia Water, evaporating to dryness, then dissolving out the inorganic salts. The pure oxide does not showdecomposition under 300 and has the formula,

' r'isO The amount of arsenic required by theory, is,

EXAMPLE 1a.-Sulfate salt of 2-hydroxy-4-amin0- phenylarsine oxide The amount found by analysis is Two grams of pure 2-hydroxy-4-aminophenylarsine oxide are dissolved in 15 ml. of 60% sul-- furic acid by warming and the solution cooled in an ice-salt bath. The sulfate precipitates in a crystalline form which decr'epitates on drying. The salt decomposes over a range of temperature but when pure is stable to 225 C. It is believed to have the formula,

.AsO

CaHeOzNAS-HzSOl NHz-HzSOa v v The amount of arsenic required by theory is 25.4%. Analysis shows the compound to contain 25.5% arsenic.

EXAMPLE 1b.Sodium salt of Z-hydro'my-elaminophenylarsine oxide Three grams of 2-hydr0xy-4-aminophenylarsine oxide are dissolved in. 15 ml. of N sodium hydroxide and 55 ml. of ethyl alcohol added. The sodium salt forms on standing. It is filtered off and dried, giving a grey-white powder.

ONa

OH CeH ;NAsNa NH: The theory requires 33.6% arsenic. 33.5%

arsenic was found.

2.2-hydroxy-4-carbethoa:yamino- EXAMPLE.

' phenylarsine dichloride EXAMPLE 3.2-hydroa:y-4 carbo-n-propoxy-' aminophenylarsine dichloride This compound is prepared in a manner essentially identical to Example 2 from 2-hydroxy-4- carbo-n-propoxyaminophenyl arsenic acid.

EXAMPLE 4.-2 -hydro:ry-4-carbobenzorcyphenylarsine dichloride This compound is formed by the reaction of Example 2 on 2-hydroxy-4-carbobenzoxyaminophenylarsonic acid.

EXAMPLE 5.-2-hydro.ry-4-carbeth0xyamin0- phenylarsine oxide The ether solution of the dichlorarsine of EX- arnple 2 (2-hydroxy-4-carbethoxyaminophenylarsine dichloride) is shaken with'50 m1. of wa- The suspension is cooled in an.

The diter, the ether evaporated and the curdy, white oxide filtered off and dried. It is sufficiently pure for most purposes. It may be purified further by solution in alkali, charcoaling, filterin and reprecipitating with acid. The compound forms a white powder melting at 161 0.

Analysis shows the compound to contain 27.92% arsenic. The formula above requires 27.63%

arsenic.

aminophenylarsine oxide The ether solution of the dichlorarsine of Example 3 is treated as in Example 5 giving 2-hydroxy 4 carbo-n -,propoxyaminophenylarsine oxide, a white powder, M. P. 201 C.

jtrso C mHmOAASN v This compound contains 26.58% arsenic as compared to 26.28% required by the formula.

EXAMPLE 7.2-hydroa:y-4-carbobenzo:cy-

aminophenylarsine oxide The ether solution of dichlorarsine of Example 4 is treated as in Example 5. The white oxide melts at 2l'l219.

AsO

C 12 0 ANAS The compound contains 22.47% arsenic. formula requires 22.49% arsenic.

The

EXAMPLE 8.-2-p-hydroxyethoa:y-4-aminophenylarsine oxide Three grams of 2-p-hydroxyethoxy-4-amino phenylarsonic acid are suspended in 75 ml. of water and 75 ml. of 6N sulfuric acid added to give a clear solution. The solution is saturated with sulfur dioxide for 6 hours after the addition of 0.1 gram of potassium iodide. On neutralizing with ammonia water and allowing to stand overnight the oxide may be obtained as a white crystalline product, containing water of hydra tion and which melts with foaming around C.

' NH: The'product contains 28.95% arsenic as campared to atheory of; 28.!7 2 required; by the formula.

2-e-hydroxypropoxy-4-aminophenylarsine oxide This oxide. is obtained: in. the; same manner as. the ethoxy compound from 2-e.-hyd-roxyprop.oxy- 4-aminophenylarsonic. acid. It: crystallizes. with water of crystallization in white plates which foam with loss of water around 90 C.

CsHuoaNAs-Hzo OH This compound 'contains-2fl;l'-.%. As, 1251- analysis whereas; the formula requires. 273%.

EXAMBLEY' 9-2-}3-hydroa:yethoxy-4 carbethoswaminoph'enylarsine "oxide.

O CHzCHzOH CnHuOaNAS r'rn-o o-oozm The formula requires 22.10% arsenic, the product analyzes, for. 22.04%.

Inthis samemanner-other-like compounds uch. as 2i-e-hydroxypropoxy 4 car-bethox-yaminophenyla-rsoniic. acid: and Z-fi-hydroxyethoxyA- carbobenzoxy-aminophenylarsonic; acid can be reduced to their respective oxides.

2 -,8- hydroxypropoxyl-carbethoxyaminophenylarsine oxide.

.iis

-ocH2cH-0H= O uHm O sNAS ILTHC O-OC2H'5 P. 172?... white.,. 2l'..1e;%, arsenic. ioun-di (the formula requires 21.22%) and 2 ,8 hydroxyethoxyt carbobenzoxyamiriophenylarsine oxide.

.IASO" M. P. 250, white, 19.52% arsenic (the formula requires 19.60%).

EXAMPLE 10.-2-methoa:y-4-carbethoxyaminophenylarsine oxide One gram of 2-methoxy-4-carbethoxyaminophenylarsonic acid is suspended in ether at room temperature, and 05" m1. of: phosphorus, trichloride added slowly with stirring. After standing one hour, the. ether is. removed; by evaporation in a current. of. air and the oxide filtered off. Theoxide may be purified by solution in alkaline media, filtering. "and reprecipitating with acid; The oxide: is a White compound; melting at: 147

1lis0 The formula requires 26.3%. arsenic, 26.1% was found.

EXAMPLE l'l.Prepamt20n of the thioglycollates of the amine oxides Oneh-undredthmol' of. the arsine oxide is dissolved in 3 ml. of water containing- 0.02 mole of sodium hydroxide. Two hundredths mol (1 .84: g.) of thioglycollic acid is added and the solution shaken well. The solution is, then diluted to. 25 ml. with absolute ethyl alcohol and then to 50 ml. with dry ether. The disodium salt of the thioglycollate precipitates as a white: material, some cases crystalline. By this method the disodium dithioglycollatesof thefollowing oxides are" prepared:

1. Z-hydroxy-d-aminophenylarsine oxide;

2; 2-hydroxy 4 carbethoxyaminophenylarsine oxide.

3-. 2 hydroxy-4-carbo-n-propoxyaminophenylarsine oxide.

4. 2-hydroxy-4-carbobenzoxyaminophenylarsine oxide. 7

5. 2 {3'- hydroxyethoxy' carbethoxyaminophenylarsine oxide; I

6. 2'-fi-hydroxypropoxy 4 carbethoxyaminophenylarsine oxide.

'7. 2-methoxy 4 carbethoxyaminophenylarsine oxide.

8; 2 fi-hydroxyethoxy- 4 carbobenzoxyamino phenylarsine oxide.

9. 2 g hydroxyethoxy 4 e aminophenylarsine oxide. 10. 2-,8-h'ydroxypropoxy 4' aminophenylarsineoxide.

EXAMPLE 12.Thioglycolamide derivatives of:

oxides By substituting thioglycolamide for the thioglycollic acid used in Example 11, the dithioglycolamide derivatives of the oxides of Example 11 as well as of other oxides of the invention can be obtained.

The examples above given are merely illustrative of the invention which can be practiced While employing numerous variations of the materials and conditions given in detail in the examples, without departing from the essential features of the invention as described. The variations mentioned will be apparent to those skilled in the art of preparing organic arsenicals.

Examples 1, 8 and 9 give conditions which make it possible for the first time to obtain 2- hydroxy--amino-phenyl arsinoxide and derivatives thereof. One of the main features of the process used in the three examples mentioned is to use a strong mineral acid other than hydrochloric or hydrobromic acids during the reduction of the arsonic acid. I prefer to use a concentration of acid ranging from about 2 normal to 6 normal, since the rate of reaction is extremely slow below 2 N and at this concentration large quantities of unreacted arsonic acid are recovered from the reaction mixture, even after a period of several days. In the higher concentrations the reaction progresses more rapidly, but if the concentration is too high, there will be too much decomposition and formation of undesired byproducts.

The method used in Examples 1, 8 and 9 is quite sensitive to iodide concentration. With minute quantities of iodide the reaction proceeds very slowly. On the other hand, if the iodide concentration is too high, nuclear substitution of the arsonic acid occurs. I therefore prefer a concentration of iodide, such as potassium iodide, of not more than about 0.2 grams/100 m1. of solution. The optimum value is around 0.1 grams/100 ml.

The arsine oxide compounds are rather sensitive to temperatures which are too high. I therefore prefer to work with these compounds, not only in they reaction mixture in which they are produced but also when further treating them, for example, during purification, at temperatures below about 40 C. in the presence of acid media and below about 80 C. in the presence of alkalies.

In those examples, such as 2 and 10, where phosphorus .trichloride is used for reducing the arsonic acid, one can substitute phosphorus tri bromide for the phosphorus trichloride. In that case the corresponding dibromo arsine compounds are obtained. However, phosphorus triiodide is not as satisfactory since reduction of the arsonic acid goes beyond the dihalo arsine stage.

When converting the dihalo arsine compounds into their arsine oxide derivatives one can use various aqueous liquids, such as quite dilute ammonium hydroxide or dilute alkaline solutions.

The dearsonation, already mentioned, which occurs when a hydrohalic acid is present with the arsine oxide compounds makes it impractical to try to prepare hydrohalic acid salts of those arsine oxides having a free or unprotected ortho hydroxyl group. Preparation of salts of these free hydroxy derivatives with oxidizing acids, e. g. nitric acid, is also impractical because of the oxidizing action of such acids on the new arsine oxides. I therefore prefer the new class of free hydroxy substituted arsine oxides of this invention and their equivalent trivalent arsenic derivatives of the formula,

AsZ

| NHY where Z has the same values as already given for the general formula, while Y stands for hydrogen, or carboalkoxy, carboaralkoxy or the corresponding soluble amine salt group, -Y-HA, where A is an anion of a non-hydrohalic nonoxidizing organic or inorganic acid, HA.

What I claim is: 1. Organic arsenic compounds of the formula,

' l sz where X is a member of the class hydrogen, methyl and hydroxyl alkyl, Y is a member of the class hydrogen, carboalkoxy, carboaralkoxy and soluble amine'salt groups, -Y-HA,.Where A is an anion of an acid which does not chemically alter the group AsZ and AsZ represents a member of the class As=0, As Cl2,

on v .A S

As (SCH2COOM)2 and As (-SCH2-CO'NH2)2 M being a soluble salt forming group.

2. Organic arsenic compounds of the formula, I

NHY

where Y represents a member of the class hydrogen, carboalkoxy, carboaralkoxy and the soluble amine salt groups, Y-I-IA, where A is an anion of an acid which does not chemically alter the group AsZ and AsZ represents a member of the class As=O, ASC12, 

